WO2017078008A1 - Tumor therapeutic agent comprising gemcitabine liposome composition and kit - Google Patents
Tumor therapeutic agent comprising gemcitabine liposome composition and kit Download PDFInfo
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Abstract
Description
タキサン系抗腫瘍剤単剤での抗腫瘍効果が低い原因の一つとして、腫瘍ごとのタキサン感受性が大きく異なり、治療患者の奏効率が上がらないことが挙げられる。そのため、タキサン系抗腫瘍剤に加えて、メカニズムが異なる抗腫瘍剤との併用が必要である。
また、非特許文献3および非特許文献1に記載されている併用療法についても、治療効果として十分に高いとは言えない。
本発明の課題は、上市されているゲムシタビン、タキサン系抗腫瘍剤およびそれらの併用療法と比較して、抗腫瘍効果に優れた腫瘍治療剤および腫瘍治療用キットを提供することである。 One of the causes of the low antitumor effect of gemcitabine alone is the short residence time of gemcitabine in blood. Gemcitabine has a strong drug effect in a time-dependent manner, but it has a short residence time in blood of 20 minutes, so that it cannot exert a sufficient antitumor effect. Another cause of the low antitumor effect of gemcitabine alone is the low selectivity of gemcitabine for tumor tissues. When an antitumor agent is administered, it may disappear quickly from the blood or be distributed to organs other than the target, and it does not always effectively accumulate in the tumor tissue. For this reason, many of the antitumor agents cannot sufficiently exert an antitumor effect on the tumor tissue, and often have an undesirable effect on normal tissues (side effects), causing serious toxicity.
One reason for the low antitumor effect of a single taxane antitumor agent is that the sensitivity of taxanes varies greatly from tumor to tumor, and the response rate of the treated patient does not increase. Therefore, in addition to the taxane antitumor agent, it is necessary to use in combination with an antitumor agent having a different mechanism.
In addition, the combination therapy described in Non-Patent Document 3 and Non-Patent Document 1 cannot be said to have a sufficiently high therapeutic effect.
An object of the present invention is to provide a tumor therapeutic agent and a tumor treatment kit superior in antitumor effect as compared with commercially available gemcitabine, a taxane antitumor agent and a combination therapy thereof.
(2)タキサン系抗腫瘍剤がパクリタキセルもしくはその塩またはナブパクリタキセルである、(1)に記載の腫瘍治療剤。
(3)タキサン系抗腫瘍剤がナブパクリタキセルである、(1)または(2)に記載の腫瘍治療剤。
(4)リポソームを構成する脂質の合計量に対するコレステロール類の含有率が10mol%~35mol%であり、リポソームの内水相の浸透圧がリポソームの外水相の浸透圧に対して2倍~8倍である、(1)~(3)のいずれか一に記載の腫瘍治療剤。
(5)リポソームがシングルラメラである(1)~(4)のいずれか一に記載の腫瘍治療剤。
(6)血漿中におけるリポソーム組成物からのゲムシタビンまたはその塩の放出速度が10質量%/24hr~70質量%/24hrである、(1)~(5)のいずれか一に記載の腫瘍治療剤。
(7)リポソームを構成する脂質が水素添加大豆ホスファチジルコリン、1、2-ジステアロイル-3-ホスファチジルエタノールアミン-ポリエチレングリコール、およびコレステロールを含む、(1)~(6)のいずれか一に記載の腫瘍治療剤。
(8)リポソームの平均粒子径が2nm~200nmである、(1)~(7)のいずれか一に記載の腫瘍治療剤。
(9)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物およびタキサン系抗腫瘍剤を含む腫瘍治療用キット。 (1) A tumor therapeutic agent comprising a combination of a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent.
(2) The tumor therapeutic agent according to (1), wherein the taxane antitumor agent is paclitaxel or a salt thereof or nabupaclitaxel.
(3) The tumor therapeutic agent according to (1) or (2), wherein the taxane antitumor agent is nabupaclitaxel.
(4) The cholesterol content relative to the total amount of lipids constituting the liposome is 10 mol% to 35 mol%, and the osmotic pressure of the inner aqueous phase of the liposome is 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome. The tumor therapeutic agent according to any one of (1) to (3), which is doubled.
(5) The tumor therapeutic agent according to any one of (1) to (4), wherein the liposome is a single lamellar.
(6) The tumor therapeutic agent according to any one of (1) to (5), wherein the release rate of gemcitabine or a salt thereof from the liposome composition in plasma is 10% by mass / 24 hr to 70% by mass / 24 hr. .
(7) The tumor according to any one of (1) to (6), wherein the lipid constituting the liposome comprises hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol Therapeutic agent.
(8) The tumor therapeutic agent according to any one of (1) to (7), wherein the liposome has an average particle size of 2 nm to 200 nm.
(9) A tumor treatment kit comprising a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent.
(10)タキサン系抗腫瘍剤から選択される1以上の抗腫瘍剤と組み合わせて併用投与されるように用いられることを特徴とする、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を含む抗腫瘍効果増強剤。
(11)タキサン系抗腫瘍剤がパクリタキセルもしくはその塩またはナブパクリタキセルである、(10)に記載の抗腫瘍効果増強剤。
(12)タキサン系抗腫瘍剤がナブパクリタキセルである、(10)または(11)に記載の抗腫瘍効果増強剤。
(13)リポソームを構成する脂質の合計量に対するコレステロール類の含有率が10mol%~35mol%であり、リポソームの内水相の浸透圧がリポソームの外水相の浸透圧に対して2倍~8倍である、(10)~(12)のいずれか一に記載の抗腫瘍効果増強剤。
(14)リポソームがシングルラメラである、(10)~(13)のいずれか一に記載の抗腫瘍効果増強剤。
(15)血漿中におけるリポソーム組成物からのゲムシタビンまたはその塩の放出速度が10質量%/24hr~70質量%/24hrである、(10)~(14)のいずれか一に記載の抗腫瘍効果増強剤。
(16)リポソームを構成する脂質が水素添加大豆ホスファチジルコリン、1、2-ジステアロイル-3-ホスファチジルエタノールアミン-ポリエチレングリコール、およびコレステロールを含む、(10)~(15)のいずれか一に記載の抗腫瘍効果増強剤。
(17)リポソームの平均粒子径が2nm~200nmである、(10)~(16)のいずれか一項に記載の抗腫瘍効果増強剤。 The present invention also provides the following.
(10) An anti-tumor composition comprising a liposome composition containing gemcitabine or a salt thereof encapsulated in a liposome, wherein the anti-tumor agent is used in combination with one or more antitumor agents selected from taxane antitumor agents Tumor effect enhancer.
(11) The antitumor effect enhancer according to (10), wherein the taxane antitumor agent is paclitaxel or a salt thereof or nabupaclitaxel.
(12) The antitumor effect enhancer according to (10) or (11), wherein the taxane antitumor agent is nabupaclitaxel.
(13) The cholesterol content relative to the total amount of lipids constituting the liposome is 10 mol% to 35 mol%, and the osmotic pressure of the inner aqueous phase of the liposome is 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome. The antitumor effect potentiator according to any one of (10) to (12), which is doubled.
(14) The antitumor effect potentiator according to any one of (10) to (13), wherein the liposome is a single lamellar.
(15) The antitumor effect according to any one of (10) to (14), wherein the release rate of gemcitabine or a salt thereof from the liposome composition in plasma is 10% by mass / 24 hr to 70% by mass / 24 hr. Enhancer.
(16) The antitumor according to any one of (10) to (15), wherein the lipid constituting the liposome comprises hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol. Tumor effect enhancer.
(17) The antitumor effect enhancer according to any one of (10) to (16), wherein the liposome has an average particle diameter of 2 nm to 200 nm.
(18)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を併用治療に用いる場合の治療有効用量、および、タキサン系抗腫瘍剤を併用治療に用いる場合の治療有効用量を組み合わせて、対象に投与することを特徴とする、腫瘍の治療方法。
(19)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を併用治療に用いる場合の治療有効用量、および、タキサン系抗腫瘍剤を併用治療に用いる場合の治療有効用量を、同時に、別々に、連続して、あるいは間隔をあけて、対象に投与することを特徴とする、腫瘍の治療方法。 Furthermore, the present invention provides the following.
(18) A therapeutically effective dose when a liposome composition containing gemcitabine or a salt thereof encapsulated in a liposome is used in combination therapy, and a therapeutically effective dose when a taxane antitumor agent is used in combination therapy, and administered to a subject A method for treating a tumor, comprising:
(19) A therapeutically effective dose when a liposome composition containing gemcitabine or a salt thereof encapsulated in a liposome is used in combination therapy, and a therapeutically effective dose when a taxane antitumor agent is used in combination therapy, simultaneously and separately. A method for treating a tumor, comprising administering to a subject continuously or at intervals.
(20)リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物とタキサン系抗腫瘍剤から選択される1以上の抗腫瘍剤とを組み合わせてなる腫瘍治療剤を製造するための、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物の使用。
(21)タキサン系抗腫瘍剤から選択される1以上の抗腫瘍剤と組み合わせて併用投与されるように用いられることを特徴とする、腫瘍治療のための、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物。 Furthermore, the present invention provides the following.
(20) Gemcitabine or a liposome thereof for producing a tumor therapeutic agent comprising a combination of a liposome composition containing gemcitabine or a salt thereof in a liposome and one or more antitumor agents selected from taxane antitumor agents Use of a liposome composition encapsulating a salt.
(21) Gemcitabine or a salt thereof is encapsulated in a liposome for tumor treatment, wherein the liposome is used in combination with one or more antitumor agents selected from taxane antitumor agents Liposome composition.
本発明において、特にことわらない限り、%は、質量百分率を意味する。
本明細書において組成物中の各成分の量は、組成物中に各成分に該当する物質が複数存在する場合、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。 In the present specification, a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
In the present invention, unless otherwise specified,% means mass percentage.
In the present specification, the amount of each component in the composition means the total amount of the plurality of substances present in the composition unless there is a specific notice when there are a plurality of substances corresponding to each component in the composition. To do.
「放出速度」とは、単位時間あたりに、リポソームに内包された薬物が、リポソームを構成する脂質膜を通過して、リポソームの外部へ出る量を意味する。
「血中滞留性」とは、リポソーム組成物を投与した対象において、リポソームに内包された状態の薬物が血液中に存在する性質を意味する。
「リポソームの平均粒子径」とは、リポソーム組成物中に存在するリポソームの体積平均粒子径を意味する。本発明のリポソーム組成物中に含まれるリポソームの平均粒子径は動的光散乱法を用いて測定する。動的光散乱を用いた市販の測定装置としては、濃厚系粒子アナライザーFPAR-1000(大塚電子社製)、ナノトラックUPA(日機装社製)およびナノサイザー(マルバーン社製)等が挙げられる。
「対象」とは、その予防若しくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防若しくは治療を必要とするヒトである。
「腫瘍」としては、例えば、乳癌、子宮体癌、卵巣癌、前立腺癌、肺癌、胃(胃腺)癌、非小細胞肺癌、膵臓癌、頭頚部扁平上皮癌、食道癌、膀胱癌、メラノーマ、大腸癌、腎細胞癌、非ホジキンリンパ腫および尿路上皮癌等が挙げられる。 “Release” means that the drug encapsulated in the liposome passes through the lipid membrane constituting the liposome and exits from the liposome.
“Release rate” means the amount of drug encapsulated in the liposome per unit time through the lipid membrane constituting the liposome and out of the liposome.
“Retention in the blood” means the property that a drug encapsulated in liposomes exists in blood in a subject administered with a liposome composition.
The “average particle diameter of the liposome” means the volume average particle diameter of the liposome present in the liposome composition. The average particle size of the liposomes contained in the liposome composition of the present invention is measured using a dynamic light scattering method. Examples of commercially available measuring apparatuses using dynamic light scattering include a dense particle analyzer FPAR-1000 (manufactured by Otsuka Electronics Co., Ltd.), Nanotrack UPA (manufactured by Nikkiso Co., Ltd.), and nanosizer (manufactured by Malvern).
The “subject” is a mammal such as a human, a mouse, a monkey, a domestic animal or the like in need of the prevention or treatment, and preferably a human in need of the prevention or treatment.
Examples of the “tumor” include breast cancer, endometrial cancer, ovarian cancer, prostate cancer, lung cancer, stomach (gastric gland) cancer, non-small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, esophageal cancer, bladder cancer, melanoma, Examples include colon cancer, renal cell carcinoma, non-Hodgkin lymphoma, and urothelial cancer.
タキサン系抗腫瘍剤としては、タキサン環またはその類縁構造を有する化合物を有効成分とする医薬組成物が挙げられる。
タキサン系抗腫瘍剤としては、具体的には、パクリタキセル、ドセタキセル、カバジタキセル、テセタキセルおよびオルタタキセル等ならびにそれらの塩または誘導体が挙げられる。
塩としては、通常知られているアミノ基などの塩基性基、ヒドロキシル基およびカルボキシル基などの酸性基における塩を挙げることができる。
塩基性基における塩としては、例えば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
酸性基における塩としては、例えば、ナトリウムおよびカリウムなどのアルカリ金属との塩;カルシウムおよびマグネシウムなどのアルカリ土類金属との塩;アンモニウム塩;ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、N、N-ジメチルアニリン、N-メチルピペリジン、N-メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、N-ベンジル-β-フェネチルアミン、1-エフェナミンおよびN、N'-ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。
パクリタキセルの誘導体としては、例えば、ナブパクリタキセル(アルブミン結合パクリタキセル)等が挙げられる。
タキサン系抗腫瘍剤としては、パクリタキセルもしくはその塩またはナブパクリタキセルが好ましく、ナブパクリタキセルがより好ましい。 (Taxane antitumor agent)
Examples of taxane antitumor agents include pharmaceutical compositions containing a taxane ring or a compound having a similar structure as an active ingredient.
Specific examples of the taxane antitumor agent include paclitaxel, docetaxel, cabazitaxel, tesetaxel and ortataxel, and salts or derivatives thereof.
Examples of the salt include generally known salts in basic groups such as amino groups, and acidic groups such as hydroxyl groups and carboxyl groups.
Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
Examples of the paclitaxel derivative include nabu paclitaxel (albumin-bound paclitaxel) and the like.
As the taxane antitumor agent, paclitaxel or a salt thereof or nabupaclitaxel is preferable, and nabupaclitaxel is more preferable.
リポソームとは、脂質を用いた脂質二重膜で形成される閉鎖小胞体であり、その閉鎖小胞の空間内に水相(内水相)を有する。内水相には、水等が含まれる。リポソームは通常、閉鎖小胞外の水溶液(外水相)に分散した状態で存在する。リポソームはシングルラメラ(単層ラメラまたはユニラメラとも呼ばれ、二重層膜が一重の構造である。)であっても、多層ラメラ(マルチラメラとも呼ばれ、タマネギ状の形状の多数の二重層膜の構造である。個々の層は水様の層で仕切られている。)であってもよいが、本発明では、医薬用途での安全性および安定性の観点から、シングルラメラのリポソームであることが好ましい。 (Liposome)
A liposome is a closed vesicle formed of a lipid bilayer membrane using lipid, and has an aqueous phase (inner aqueous phase) in the space of the closed vesicle. The inner water phase includes water and the like. Liposomes usually exist in a dispersed state in an aqueous solution outside the closed vesicles (outer aqueous phase). Liposomes are single lamellae (also called single-layer lamellae or unilamellar, and double-layer membranes have a single structure.) In the present invention, from the viewpoint of safety and stability in pharmaceutical use, it is a single-lamellar liposome. Is preferred.
本発明に係るリポソームを構成する脂質の合計量に対するコレステロール類の含有率は10mol%~35mol%であり、好ましくは15mol%~25mol%、より好ましくは17mol%~21mol%である。リポソームを構成する脂質の合計量に対するコレステロール類の含有率を10mol%~35mol%とすることにより、薬物の放出し易さと保管安定性とを両立できるリポソーム組成物を得ることができる。 In liposomes, the addition of cholesterols is expected to lower the fluidity of the liposome membrane, such as by filling gaps in the liposome membrane. In general, in liposomes, the amount of cholesterol is desirably contained in an amount usually up to about 50 mol% in the total (total lipid) mol of lipid components. However, the optimum range of the amount of cholesterol in the liposome having a high osmotic pressure in the inner aqueous phase has not been known.
The content of cholesterol with respect to the total amount of lipids constituting the liposome according to the present invention is 10 mol% to 35 mol%, preferably 15 mol% to 25 mol%, more preferably 17 mol% to 21 mol%. By setting the content of cholesterol to the total amount of lipids constituting the liposome to be 10 mol% to 35 mol%, it is possible to obtain a liposome composition that can achieve both drug release and storage stability.
これらの中でも、製剤の血中滞留性の観点から、ポリエチレングリコール類、ポリグリセリン類およびポリプロピレングリコール類が好ましく、ポリエチレングリコール(PEG)、ポリグリセリン(PG)およびポリプロピレングリコール(PPG)がより好ましい。汎用性および血中滞留性の観点から、ポリエチレングリコール(PEG)がさらに好ましい。 Examples of the hydrophilic polymer include polyethylene glycols, polyglycerins, polypropylene glycols, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, polyvinyl pyrrolidone, and synthetic polyamino acid. Said hydrophilic polymer can be used individually or in combination of 2 types or more, respectively.
Among these, polyethylene glycols, polyglycerols and polypropylene glycols are preferable from the viewpoint of blood retention of the preparation, and polyethylene glycol (PEG), polyglycerol (PG) and polypropylene glycol (PPG) are more preferable. From the viewpoint of versatility and blood retention, polyethylene glycol (PEG) is more preferable.
本発明に係るリポソームは、薬物として少なくともゲムシタビンまたはその塩を内包する。
ゲムシタビンの塩としては、通常知られているアミノ基などの塩基性基、ヒドロキシル基およびカルボキシル基などの酸性基における塩を挙げることができる。
塩基性基における塩としては、例えば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
酸性基における塩としては、例えば、ナトリウムおよびカリウムなどのアルカリ金属との塩;カルシウムおよびマグネシウムなどのアルカリ土類金属との塩;アンモニウム塩;ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、N、N-ジメチルアニリン、N-メチルピペリジン、N-メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、N-ベンジル-β-フェネチルアミン、1-エフェナミンおよびN、N'-ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。
ゲムシタビンの塩としては、塩酸塩が好ましい。
ゲムシタビンの含有量は、リポソーム組成物に対して0.1~2.0mg/mlであることが好ましく、0.2~1.0mg/mlであることがより好ましい。 (Drug)
The liposome according to the present invention includes at least gemcitabine or a salt thereof as a drug.
Examples of the salt of gemcitabine include a salt of a commonly known basic group such as an amino group and an acidic group such as a hydroxyl group and a carboxyl group.
Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
As the salt of gemcitabine, hydrochloride is preferable.
The content of gemcitabine is preferably 0.1 to 2.0 mg / ml, more preferably 0.2 to 1.0 mg / ml with respect to the liposome composition.
本発明に係るリポソームに内包された薬物(ゲムシタビンまたはその塩)は、リポソームの内水相に溶解状態で存在している。ここで、溶解状態とは、リポソームの体積に対して充填した薬物の量が、その内水相の組成液での薬物の飽和溶解度以下の場合、溶解状態で内包されたものとみなす。また、飽和溶解度以上においても、Cryo-TEMで薬物結晶が観察されない、またはXRD測定で結晶格子に起因する回折パターンが観察されない場合、リポソームに内包された薬物の大部分が溶解し、溶解状態で内包されたものとみなす。この場合、脂質膜が作る物理化学的な環境による溶解促進、または一部薬物が脂質膜に取り込み等が起きていると推測する。 (Drug included in dissolved state)
The drug (gemcitabine or a salt thereof) encapsulated in the liposome according to the present invention exists in a dissolved state in the internal aqueous phase of the liposome. Here, the dissolved state is considered to be encapsulated in the dissolved state when the amount of the drug filled with respect to the volume of the liposome is equal to or lower than the saturated solubility of the drug in the composition solution of the inner aqueous phase. In addition, even when the solubility is higher than the saturation solubility, when no drug crystals are observed with Cryo-TEM, or when the diffraction pattern due to the crystal lattice is not observed with XRD measurement, most of the drugs encapsulated in the liposomes are dissolved and dissolved. Considered to be included. In this case, it is assumed that dissolution is promoted by the physicochemical environment created by the lipid membrane, or that some drugs are incorporated into the lipid membrane.
本発明に係るリポソーム組成物は、ゲムシタビンまたはその塩を内包するリポソームおよびそのリポソームを分散する水溶液を含むことができる。 (Liposome composition)
The liposome composition according to the present invention can include a liposome encapsulating gemcitabine or a salt thereof and an aqueous solution in which the liposome is dispersed.
本発明に係るリポソーム組成物において、薬物(ゲムシタビンまたはその塩)の放出速度は10質量%/24hr~70質量%/24hrが好ましく、20質量%/24hr~60質量%/24hrがより好ましく、20質量%/24hr~50質量%/24hrがさらに好ましい。 (Release rate)
In the liposome composition according to the present invention, the release rate of the drug (gemcitabine or a salt thereof) is preferably 10% by mass / 24 hr to 70% by mass / 24 hr, more preferably 20% by mass / 24 hr to 60% by mass / 24 hr, More preferably, the content is from mass% / 24 hr to 50 mass% / 24 hr.
本発明に係るリポソーム組成物は、
乾燥固化工程を経ずに、有機溶媒に溶解した脂質を乳化してリポソームを形成する乳化工程、
乳化工程で得られたリポソームにゲムシタビンまたはその塩を内包させる薬物ローディング工程、および
リポソームの内水相の浸透圧をリポソームの外水相の浸透圧に対して2倍~8倍に調整する浸透圧調整工程
を含む方法により製造することができる。
リポソーム組成物の製造方法は、必要に応じて、乳化工程で用いた有機溶媒を蒸発させる蒸発工程、無菌ろ過、無菌充填等の他の工程を含んでもよい。 (Method for producing liposome composition)
The liposome composition according to the present invention comprises:
An emulsification step in which a lipid is dissolved in an organic solvent to form liposomes without going through a drying and solidification step.
Drug loading step in which gemcitabine or a salt thereof is encapsulated in the liposome obtained in the emulsification step, and osmotic pressure for adjusting the osmotic pressure of the inner aqueous phase of the liposome to 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome It can be manufactured by a method including an adjusting step.
The method for producing a liposome composition may include other steps such as an evaporation step for evaporating the organic solvent used in the emulsification step, aseptic filtration, and aseptic filling, as necessary.
乳化工程では、少なくとも1種の脂質が有機溶媒に溶解している油相と水相とを混合して脂質を含む水溶液を攪拌して乳化することができる。脂質が有機溶媒に溶解している油相および水相を混合し撹拌し、乳化することで、油相および水相がO/W型に乳化した乳化液が調製される。混合後、油相由来の有機溶媒の一部または全部を後述する蒸発工程によって除去することにより、リポソームが形成される。または、油相中の有機溶媒の一部または全部が撹拌・乳化の過程で蒸発して、リポソームが形成される。 (Emulsification process)
In the emulsification step, an oil phase in which at least one kind of lipid is dissolved in an organic solvent and an aqueous phase are mixed, and an aqueous solution containing the lipid can be stirred and emulsified. By mixing, stirring and emulsifying the oil phase and the aqueous phase in which the lipid is dissolved in the organic solvent, an emulsion in which the oil phase and the aqueous phase are emulsified in the O / W type is prepared. After mixing, liposomes are formed by removing part or all of the organic solvent derived from the oil phase by the evaporation step described below. Alternatively, part or all of the organic solvent in the oil phase evaporates in the course of stirring and emulsification to form liposomes.
油相として用いられる有機溶媒として、水溶性有機溶媒およびエステル系有機溶媒の混合溶媒を用いる。本発明では、有機溶媒として、クロロホルム、塩化メチレン、ヘキサン、およびシクロヘキサン等の有機溶剤を実質的に用いないことが好ましく、これらの有機溶剤をまったく用いないことがより好ましい。 (Oil phase)
As the organic solvent used as the oil phase, a mixed solvent of a water-soluble organic solvent and an ester organic solvent is used. In the present invention, it is preferable that substantially no organic solvents such as chloroform, methylene chloride, hexane, and cyclohexane are used as the organic solvent, and it is more preferable that these organic solvents are not used at all.
水相とは、外水相および内水相を意味する。
本発明における外水相とは、リポソームを分散する水溶液を意味する。例えば注射剤の場合においては、バイアル瓶またはプレフィルドシリンジ包装されて保管されたリポソームの分散液のリポソームの外側を占める溶液が外水相となる。また、添付された分散用液またはその他溶解液により投与時に用時分散した液についても同様に、リポソームの分散液のリポソームの外側を占める溶液が外水相となる。
本発明における内水相とは、リポソームの脂質二重膜を隔てた閉鎖小胞内の水相を意味する。
リポソームを製造する際に、リポソームを分散する水溶液(外水相)としては、水(蒸留水、注射用水等)、生理食塩水、各種緩衝液または糖類の水溶液およびこれらの混合物(水性溶媒)が好ましく用いられる。緩衝液としては、有機系、無機系に限定されることはないが、体液に近い水素イオン濃度付近に緩衝作用を有する緩衝液が好適に用いられ、リン酸緩衝液、トリス緩衝液、クエン酸緩衝液、酢酸緩衝液およびグッドバッファー等があげられる。水相のpHは、例えば、5~9とすることができ、7~8であることが好ましい。リポソームを分散する水溶液(外水相)としては、リン酸緩衝液(例えば、pH=7.4)を用いることが好ましい。リポソームの内水相は、リポソームを製造する際に、リポソームを分散する水溶液であってもよいし、新たに添加される、水、生理食塩水、各種緩衝液または糖類の水溶液およびこれらの混合物をあってもよい。外水相または内水相として用いる水は、不純物(埃、化学物質等)を含まないことが好ましい。
生理食塩水とは、人体と等張になるように調整された無機塩溶液を意味し、さらに緩衝機能を持っていてもよい。生理食塩水としては、塩化ナトリウムを0.9w/v%含有する食塩水、リン酸緩衝生理食塩水(以下、PBSともいう)およびトリス緩衝生理食塩水等が挙げられる。 (Water phase)
The aqueous phase means an outer aqueous phase and an inner aqueous phase.
The outer aqueous phase in the present invention means an aqueous solution in which liposomes are dispersed. For example, in the case of an injection, a solution occupying the outside of the liposome in a dispersion of liposomes stored in a vial or prefilled syringe package is the outer aqueous phase. Similarly, the solution occupying the outside of the liposome in the liposome dispersion is the outer aqueous phase of the dispersion dispersed at the time of administration using the attached dispersion or other solution.
The inner aqueous phase in the present invention means an aqueous phase in a closed vesicle separated by a lipid bilayer of a liposome.
The aqueous solution (outer aqueous phase) in which the liposomes are dispersed in the production of liposomes includes water (distilled water, water for injection, etc.), physiological saline, various buffer solutions or aqueous solutions of saccharides, and mixtures thereof (aqueous solvent). Preferably used. The buffer is not limited to organic or inorganic, but a buffer having a buffering action near the hydrogen ion concentration close to the body fluid is preferably used. Phosphate buffer, Tris buffer, citric acid Examples include a buffer solution, an acetate buffer solution, and a good buffer. The pH of the aqueous phase can be, for example, 5 to 9, and preferably 7 to 8. As an aqueous solution (outer aqueous phase) in which the liposome is dispersed, a phosphate buffer solution (for example, pH = 7.4) is preferably used. The internal aqueous phase of the liposome may be an aqueous solution in which the liposome is dispersed when the liposome is produced, or water, physiological saline, various buffer solutions or aqueous solutions of saccharides and a mixture thereof newly added. There may be. It is preferable that the water used as the outer aqueous phase or the inner aqueous phase does not contain impurities (dust, chemical substances, etc.).
The physiological saline means an inorganic salt solution adjusted to be isotonic with the human body, and may further have a buffer function. Examples of the physiological saline include saline containing 0.9 w / v sodium chloride, phosphate buffered saline (hereinafter also referred to as PBS), Tris buffered saline, and the like.
エクストリュージョン処理とは、細孔を有するフィルターにリポソームを通過させることで、物理的なせん断力を施し、微粒化する工程を意味する。リポソームを通過させる際、リポソーム分散液およびフィルターを、リポソームを構成する膜の相転移温度以上の温度に保温することで、速やかに微粒化することができる。 (Extrusion processing)
The extrusion treatment means a step of applying physical shearing force and atomizing by passing the liposome through a filter having pores. When passing the liposome, the liposome dispersion liquid and the filter can be rapidly atomized by keeping the temperature at a temperature higher than the phase transition temperature of the membrane constituting the liposome.
リポソーム組成物の製造方法においては、必要に応じて蒸発工程を設けてもよい。蒸発工程では、乳化工程で得られたリポソームを含む水溶液から有機溶媒を蒸発させる。本発明において、蒸発工程とは、油相由来の有機溶媒の一部または全部を蒸発工程として強制的に除去する工程、および油相中の有機溶媒の一部または全部が撹拌・乳化の過程で自然に蒸発する工程の少なくとも一つを含む。 (Evaporation process)
In the method for producing a liposome composition, an evaporation step may be provided as necessary. In the evaporation step, the organic solvent is evaporated from the aqueous solution containing the liposomes obtained in the emulsification step. In the present invention, the evaporation step is a step in which part or all of the organic solvent derived from the oil phase is forcibly removed as an evaporation step, and a portion or all of the organic solvent in the oil phase is a process of stirring and emulsification. Including at least one of the steps of spontaneous evaporation.
有機溶剤を蒸発させる工程において、リポソームを含む水溶液に含まれる有機溶媒の濃度を、有機溶剤を蒸発させる工程の開始後から30分以内に、15質量%以下にすることが好ましい。 The method for evaporating the organic solvent in the evaporation step is not particularly limited. For example, the step of evaporating the organic solvent by heating, the step of continuing static stirring or gentle stirring after emulsification, and the step of performing vacuum deaeration Do at least one.
In the step of evaporating the organic solvent, the concentration of the organic solvent contained in the aqueous solution containing the liposome is preferably 15% by mass or less within 30 minutes after the start of the step of evaporating the organic solvent.
薬物ローディング工程では、リポソームに薬物(ゲムシタビンまたはその塩)を内包させる場合、水和・膨潤させる水性媒体に薬物を溶解し、相転移温度以上の加熱、超音波処理またはエクストルージョン等の方法により薬物をリポソームの内水相に内包させることができる。また、脂質乳化時の水相に薬物を溶解させ内水相に内包させることもできる。 (Drug loading process)
In the drug loading step, when the drug (gemcitabine or a salt thereof) is encapsulated in the liposome, the drug is dissolved in an aqueous medium to be hydrated and swollen, and the drug is obtained by a method such as heating above the phase transition temperature, sonication or extrusion. Can be encapsulated in the internal aqueous phase of the liposome. Alternatively, the drug can be dissolved in the aqueous phase during lipid emulsification and encapsulated in the inner aqueous phase.
浸透圧調整工程とは、リポソームの内水相および外水相の浸透圧を調整する工程を意味する。リポソームの内水相および外水相の浸透圧を調整することにより、放出速度を制御することができる。浸透圧調整工程としては、特に限定されないが、透析等が挙げられる。本発明の製造方法では、核酸アナログ抗癌剤をリポソームに内包させる工程および浸透圧調整工程を同時に行うことが、生産効率の観点から好ましい。 (Osmotic pressure adjustment process)
The osmotic pressure adjusting step means a step of adjusting the osmotic pressure of the inner aqueous phase and the outer aqueous phase of the liposome. The release rate can be controlled by adjusting the osmotic pressure of the inner aqueous phase and the outer aqueous phase of the liposome. Although it does not specifically limit as an osmotic pressure adjustment process, Dialysis etc. are mentioned. In the production method of the present invention, it is preferable from the viewpoint of production efficiency to simultaneously perform the step of encapsulating the nucleic acid analog anticancer agent in liposomes and the osmotic pressure adjustment step.
リポソームの内水相の浸透圧をリポソームの外水相の浸透圧に対して2倍~8倍に調整することが好ましく、2.5倍~6倍に調整することがより好ましく、3倍~5倍に調整することがさらに好ましい。 In the liquid obtained after the drug loading step, the solutes of the outer aqueous phase and the inner aqueous phase are homogenized, and the osmotic pressure at that time can be defined as the osmotic pressure of the inner aqueous phase of the completed liposome. However, in the subsequent substitution / osmotic pressure adjustment step by dialysis of the outer aqueous phase, the heating operation is limited to the case where the solute of the inner aqueous phase is sufficiently retained, for example, by suppressing it to a phase transition of lipid or less. The osmotic pressure of the outer aqueous phase can be defined by the osmotic pressure of the dialysate used in the final dialysis step. However, this is limited to the case where the dialysate can be sufficiently replaced. In addition, using a centrifugal separation or ultrafiltration, the solute composition concentration of the outer aqueous phase and the solute composition concentration of the inner aqueous phase are quantified and the osmotic pressure of the composition solution is measured. In particular, the osmotic pressure of the inner aqueous phase and the outer aqueous phase can be obtained.
The osmotic pressure of the inner aqueous phase of the liposome is preferably adjusted to 2 to 8 times, more preferably adjusted to 2.5 to 6 times the osmotic pressure of the outer aqueous phase of the liposome, more preferably 3 to It is more preferable to adjust to 5 times.
リポソーム組成物は、無菌ろ過を行うことが好ましい。ろ過の方法としては、中空糸膜、逆浸透膜またはメンブレンフィルター等を用いて、リポソームを含む水溶液から不要な物を除去することができる。本発明では、滅菌できる孔径をもつフィルター(好ましくは0.2μmのろ過滅菌フィルター)によってろ過することが好ましい。 (Aseptic filtration)
The liposome composition is preferably subjected to aseptic filtration. As a filtration method, an unnecessary thing can be removed from the aqueous solution containing a liposome using a hollow fiber membrane, a reverse osmosis membrane, or a membrane filter. In the present invention, it is preferable to filter with a filter having a pore size that can be sterilized (preferably a 0.2 μm filter sterilization filter).
無菌ろ過の後に得られたリポソーム組成物は、医療用途として無菌充填することが好ましい。無菌充填の方法は公知のものが適用できる。容器に無菌的に充填することで医療用として好適なリポソーム組成物が調製できる。 (Aseptic filling)
The liposome composition obtained after aseptic filtration is preferably aseptically filled for medical use. A known method can be applied for aseptic filling. A liposome composition suitable for medical use can be prepared by filling the container aseptically.
本発明の腫瘍治療剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤および吸収促進剤などの添加剤を含んでいてもよい。 (Tumor therapeutic agent)
The tumor therapeutic agent of the present invention is usually an excipient, binder, lubricant, disintegrant, coloring agent, flavoring agent, emulsifier, surfactant, solubilizing agent, suspending agent used for formulation. Additives such as agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物とタキサン系抗腫瘍剤とが別個の製剤からなる腫瘍治療剤を用いる場合には、各製剤は、同時に、別々に、連続して、あるいは間隔をあけて対象に投与することができる。 The tumor therapeutic agent of the present invention includes a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a liposomal composition in which gemcitabine or a salt thereof is encapsulated in a liposome, even if it is a one-part preparation containing a taxane antitumor agent. It may be a two-drug preparation of a product and a taxane antitumor agent. Preferably, it is a two-drug preparation comprising a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent as separate preparations.
When using a tumor therapeutic agent comprising a liposome composition in which liposome is encapsulated in gemcitabine or a salt thereof and a taxane antitumor agent, each formulation is simultaneously, separately, sequentially, or spaced apart. Can be administered to a subject with a gap.
リポソーム組成物の投与経路としては、非経口投与が好ましい。例えば、点滴等の静脈内注射(静注)、筋肉内注射、腹腔内注射、皮下注射、眼内注射および髄腔内注射を挙げることができる。投与方法としては、シリンジまたは点滴による投与が挙げられる。
タキサン系抗腫瘍剤の投与経路としては、経口投与が好ましい。
本発明の腫瘍治療剤においては、例えば、リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物を非経口投与し、タキサン系抗腫瘍剤を経口投与することができる。 Examples of the administration route of the tumor therapeutic agent of the present invention include intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration, and suppository. Is mentioned.
As an administration route of the liposome composition, parenteral administration is preferable. For example, intravenous injection (intravenous injection) such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection can be mentioned. Examples of the administration method include administration by syringe or infusion.
The administration route of the taxane antitumor agent is preferably oral administration.
In the tumor therapeutic agent of the present invention, for example, a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome can be administered parenterally, and a taxane antitumor agent can be administered orally.
タキサン系抗腫瘍剤の投与量および投与回数は、例えば、成人に対しては、1日あたり、0.01mg/kg~1000mg/kgを1回から数回に分割して投与することができる。 The dosage and administration frequency of gemcitabine or a salt thereof contained in the liposome composition can be administered in 1 to 4 mg / kg divided into 1 to several times per day. For example, in the case of an injection, it is preferable that 60 mg to 240 mg, preferably 120 mg to 240 mg, more preferably 180 mg to 240 mg per day is administered by intravenous injection in a human (patient; weight 60 kg). However, the dose and the number of administration are not limited.
Regarding the dosage and frequency of administration of the taxane antitumor agent, for example, 0.01 mg / kg to 1000 mg / kg can be divided into 1 to several times per day for an adult.
本発明のキットは、(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤の組み合わせからなるキットである。
本発明のキットでは、(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤は各々公知の各種の製剤形態とすることができ、その製剤形態に応じて、通常用いられる各種の容器に収容される。
本発明のキットでは、(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤は各々別の容器に収容されてもよいし、混合されて同じ容器に収容されてもよい。(a)ゲムシタビンまたはその塩を内包したリポソーム組成物および(b)タキサン系抗腫瘍剤が各々別の容器に収容されていることが好ましい。 (kit)
The kit of the present invention is a kit comprising a combination of (a) a liposome composition encapsulating gemcitabine or a salt thereof and (b) a taxane antitumor agent.
In the kit of the present invention, (a) a liposome composition encapsulating gemcitabine or a salt thereof and (b) a taxane antitumor agent can each be in various known dosage forms, and depending on the dosage form, Housed in various containers used.
In the kit of the present invention, (a) the liposome composition containing gemcitabine or a salt thereof and (b) the taxane antitumor agent may be contained in separate containers, or may be mixed and contained in the same container. Also good. It is preferable that (a) a liposome composition containing gemcitabine or a salt thereof and (b) a taxane antitumor agent are contained in separate containers.
本発明の抗腫瘍効果増強剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤および吸収促進剤などの添加剤を含んでいてもよい。 (Anti-tumor effect enhancer)
The antitumor effect potentiator of the present invention is usually an excipient, a binder, a lubricant, a disintegrant, a colorant, a flavoring agent, an emulsifier, a surfactant, a solubilizing agent, a suspension, Additives such as turbidity agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
平均粒子径は、試料を1×PBS(ニッポンジーン社製)で1000倍質量に希釈し、ナノトラックUPA-UT(日機装社製)を用い、動的光散乱法で体積平均粒子径を測定した。
腫瘍体積は、腫瘍長径(a)および短径(b)をノギスで測定し、以下の式で算出した。
式:(a×b2)×0.5(式中、“a”は長径であり、“b”は短径である。) Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.
For the average particle size, the sample was diluted 1000 times with 1 × PBS (Nippon Gene), and the volume average particle size was measured by a dynamic light scattering method using Nanotrac UPA-UT (Nikkiso Co., Ltd.).
The tumor volume was calculated by the following formula, measuring the tumor major axis (a) and minor axis (b) with calipers.
Formula: (a × b 2 ) × 0.5 (wherein “a” is the major axis and “b” is the minor axis)
a)油相の調製
水素添加大豆ホスファチジルコリン、コレステロールおよびN-(カルボニル-メトキシポリエチレングリコール2000)-1、2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミンナトリウム塩(以下、DSPE-PEGともいう)を76/19/5のモル比となるようにそれぞれ16.6g、2.0g、4.3g取り、次いで有機溶媒(エタノール/酢酸エチル=3/1)405mlを加えて70℃に加温して脂質を溶解し油相とした。 (Reference Example 1)
a) Preparation of oil phase Hydrogenated soybean phosphatidylcholine, cholesterol and N- (carbonyl-methoxypolyethylene glycol 2000) -1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (hereinafter also referred to as DSPE-PEG) ) Is taken to have a molar ratio of 76/19/5, respectively, 16.6 g, 2.0 g, 4.3 g are taken, and then 405 ml of an organic solvent (ethanol / ethyl acetate = 3/1) is added and heated to 70 ° C. The lipid was dissolved to obtain an oil phase.
4mMリン酸緩衝液(pH7.78)を調製し水相とした。 b) Preparation of aqueous phase A 4 mM phosphate buffer (pH 7.78) was prepared and used as the aqueous phase.
水相を70℃に加温し、水相/油相=8/3の容積比となるように油相を添加した後、回転かき混ぜ式乳化機にて、周速20m/s、13000rpmにて30分間混合した。その後、相転位温度以上に加温しながら窒素を送気することで有機溶剤と水とを蒸発させ、乳化前の容積に対して約1/10の体積になるまで濃縮し、薬物未内包リポソームを得た。このときの平均粒子径は68.0nmであった。 c) Preparation of unencapsulated drug liposomes The aqueous phase is heated to 70 ° C., and the oil phase is added so that the volume ratio of aqueous phase / oil phase = 8/3. Mixing was performed at a speed of 20 m / s at 13000 rpm for 30 minutes. Thereafter, the organic solvent and water are evaporated by supplying nitrogen while heating above the phase transition temperature, and concentrated to about 1/10 of the volume before emulsification. Got. The average particle size at this time was 68.0 nm.
上記c)で調製した薬物未内包リポソーム2バッチを混合した。 d) Batch mixing of unencapsulated liposomes 2 batches of unencapsulated liposomes prepared in c) above were mixed.
薬物として、ゲムシタビン塩酸塩を用いた。ゲムシタビン塩酸塩はTEVA社から購入した。塩化ナトリウム81.63g、リン酸水素二ナトリウム十二水和物29.01g、リン酸二水素ナトリウム二水和物2.29gを注射用水948gで溶解し、PBSとした。二つの容器にそれぞれゲムシタビン塩酸塩12.98g、PBS54.01g、日局注射用水75.74g、8M水酸化ナトリウム2.71mLを混合し、薬物溶液とした。それぞれの薬物溶液に、薬物未封入リポソーム141.4mL、8M水酸化ナトリウム2.71mLを加え、混合した。この液の浸透圧は1039mOsm/Lであり、これが完成するリポソーム組成物の内水相の浸透圧となる。次にこの液を70℃で10分間加熱した後40℃まで冷却し、1016mMスクロース/37mMヒスチジン溶液で希釈した。希釈後、一つにまとめ、薬物ローディング液とした。透析によるリポソーム組成物の完成透析液として275mMスクロース/10mMヒスチジン水溶液を調製した。この液の溶質モル濃度より求めた浸透圧は285mOsm/Lであった。この透析液を用いて室温にて透析を行い、薬物ローディング液の外水相に存在する未封入のゲムシタビン塩酸塩と各溶質を除去し、透析液で外水相を置換した。以上の工程により、ゲムシタビン塩酸塩濃度0.81mg/mL、平均粒子径74.9nm、内水相浸透圧1039mOsm/L、外水相浸透圧285mOsm/L、内水相の外水相に対する浸透圧が3.6倍のゲムシタビン内包リポソーム組成物を得た。リポソームを構成する脂質の合計量に対するコレステロール類の含有率は19.3mol%であった。
なお、浸透圧は、溶質モル濃度から算出した。 e) Preparation of drug-encapsulating liposomes Gemcitabine hydrochloride was used as a drug. Gemcitabine hydrochloride was purchased from TEVA. 81.63 g of sodium chloride, 29.01 g of disodium hydrogen phosphate dodecahydrate and 2.29 g of sodium dihydrogen phosphate dihydrate were dissolved in 948 g of water for injection to obtain PBS. In each of the two containers, 12.98 g of gemcitabine hydrochloride, 54.01 g of PBS, 75.74 g of JP injection water, and 2.71 mL of 8M sodium hydroxide were mixed to obtain a drug solution. To each drug solution, 141.4 mL of drug-unencapsulated liposomes and 2.71 mL of 8M sodium hydroxide were added and mixed. The osmotic pressure of this liquid is 1039 mOsm / L, which becomes the osmotic pressure of the inner aqueous phase of the liposome composition to be completed. Next, this solution was heated at 70 ° C. for 10 minutes, cooled to 40 ° C., and diluted with a 1016 mM sucrose / 37 mM histidine solution. After dilution, they were combined into a drug loading solution. A 275 mM sucrose / 10 mM histidine aqueous solution was prepared as a finished dialysate of the liposome composition by dialysis. The osmotic pressure determined from the solute molar concentration of this solution was 285 mOsm / L. Dialysis was performed using this dialysate at room temperature to remove unencapsulated gemcitabine hydrochloride and each solute present in the outer aqueous phase of the drug loading solution, and the outer aqueous phase was replaced with the dialysate. Through the above steps, gemcitabine hydrochloride concentration 0.81 mg / mL, average particle diameter 74.9 nm, inner aqueous phase osmotic pressure 1039 mOsm / L, outer aqueous phase osmotic pressure 285 mOsm / L, osmotic pressure of inner aqueous phase with respect to outer aqueous phase Obtained a 3.6 times larger gemcitabine-encapsulating liposome composition. The content of cholesterol with respect to the total amount of lipid constituting the liposome was 19.3 mol%.
The osmotic pressure was calculated from the solute molar concentration.
血漿中の放出速度の測定
リポソーム組成物50μLをマウス血漿で20倍希釈(体積)し、37℃で24時間インキュベートし、24時間の時点で100μL採取した。続いて、限外ろ過フィルター(アミコンウルトラ-0.5 10kDa、ミリポア社製)を用い7400×g、30分、4℃の条件で遠心ろ過を行った。回収したろ液に含まれる薬物量をHPLCにて定量し、放出速度を次の式により算出した。
式:放出速度(%/24hr)=(インキュベーション24時間後のろ液中の薬物量)×20÷リポソーム組成物の全相に含まれる薬量×100
結果は24%/24hrであった。 (Reference Example 2)
Measurement of Release Rate in Plasma 50 μL of the liposome composition was diluted 20 times with mouse plasma (volume), incubated at 37 ° C. for 24 hours, and 100 μL was collected at 24 hours. Subsequently, centrifugal filtration was performed using an ultrafiltration filter (Amicon Ultra-0.5 10 kDa, manufactured by Millipore) at 7400 × g for 30 minutes at 4 ° C. The amount of drug contained in the collected filtrate was quantified by HPLC, and the release rate was calculated by the following formula.
Formula: Release rate (% / 24 hr) = (Amount of drug in filtrate after 24 hours of incubation) × 20 ÷ Drug amount contained in all phases of liposome composition × 100
The result was 24% / 24 hr.
Capan-1皮下移植担がんモデルマウスでの薬効試験
被験物質として、ゲムシタビン(以下、Gemともいう)、アブラキサン(以下、Abxともいう)およびゲムシタビン内包リポソーム組成物(以下、組成物Aともいう)を用いた。
Gemは、ゲムシタビン塩酸塩(TEVA社製)を生理食塩水に溶解させたものを用いた。Abxは、アブラキサン(Celgene社製)を生理食塩水に溶解させたものを用いた。ゲムシタビン内包リポソーム組成物は、参考例1で作製したものを用いた。
ヒト膵臓癌細胞株であるCapan-1細胞1×107個を雌性ヌードマウスの脇腹部皮下に移植し皮下腫瘍を形成させた。腫瘍体積を指標としてAbxおよび組成物Aの併用投与における皮下腫瘍の抑制効果を評価した。被験物質として、群1はスクロース溶液、群2はGem、群3は組成物A、群4および群5はAbxおよびGem、群6および群7はAbxおよび組成物Aを用いた。群1~5が比較例、群6および群7が実施例である。被験物質はいずれも移植後17日目から週1回、計3週間、尾静脈投与した。
なお、各薬剤の投与量は、体重減少率が20%を超えない量をMTD(最大耐用量)回復が認められないような重篤な最低体重に達しないと思われる用量として設定した。
群構成および投与量を表1に示す。 Example 1
Medicinal effect test in Capan-1 subcutaneous transplantation tumor-bearing model mouse As test substances, gemcitabine (hereinafter also referred to as Gem), abraxane (hereinafter also referred to as Abx) and gemcitabine-encapsulating liposome composition (hereinafter also referred to as composition A) Was used.
As Gem, gemcitabine hydrochloride (manufactured by TEVA) dissolved in physiological saline was used. Abx was prepared by dissolving Abraxane (Celgene) in physiological saline. As the gemcitabine-encapsulating liposome composition, the one prepared in Reference Example 1 was used.
1 × 10 7 Capan-1 cells, a human pancreatic cancer cell line, were transplanted subcutaneously into the flank of female nude mice to form subcutaneous tumors. Using the tumor volume as an index, the subcutaneous tumor suppressive effect of the combined administration of Abx and Composition A was evaluated. As test substances, group 1 used sucrose solution, group 2 used Gem, group 3 used composition A, groups 4 and 5 used Abx and Gem, group 6 and group 7 used Abx and composition A. Groups 1 to 5 are comparative examples, and groups 6 and 7 are examples. All test substances were administered via the caudal vein once a week from the 17th day after transplantation for a total of 3 weeks.
The dose of each drug was set such that the weight loss rate did not exceed 20% as a dose that would not reach a serious minimum body weight so that MTD (maximum tolerated dose) recovery was not observed.
Table 1 shows the group composition and dosage.
統計学的解析として、Tukeyの多重比較検定(Tukey's multiple comparisons test)を実施し、群間でP値5%未満を統計学的有意差ありと判定した。データ処理にはGraphpad Prism version 5.03を用いた。
表2において、aは群1との比較によりP<0.001であったものを、bは群2との比較によりP<0.001であったものを、cは群4との比較によりP<0.05であったものを示し、N.R.は退縮なしを示す。 Table 2 shows the tumor volume average value on the 38th day after transplantation, the tumor volume standard deviation on the 38th day after transplantation, the tumor regression rate from the start of administration, and the number of days to reach the tumor volume average value of 2000 mm 3 .
As a statistical analysis, Tukey's multiple comparisons test was performed, and a P value of less than 5% was determined to be statistically significant between groups. Graphpad Prism version 5.03 was used for data processing.
In Table 2, a is P <0.001 by comparison with Group 1, b is P <0.001 by comparison with Group 2, c is by comparison with Group 4. P <0.05. R. Indicates no retraction.
以上の結果から、組成物AはAbxとの併用においてヌードマウスの皮下に移植したCapan-1腫瘍細胞の増殖抑制効果を有し、その増殖抑制効果はGemとAbxとの併用よりも上回ることが示された。 In group 6 or group 7, the tumor volume was smaller at 38 days after transplantation compared to group 4 or group 5, and group 6 showed a statistically significant difference from group 4 (P <0.05). ). Regarding the tumor regression rate from the start of administration, no tumor regression was observed in Group 4, and the tumor regression rate in Group 5 was 31%, whereas the tumor regression rate in Group 6 was 47%. %, The tumor regression rate in group 7 was 86%, and group 6 and group 7 showed an excellent tumor regression effect. Furthermore, the arrival time to a tumor volume average of 2000 mm 3 is 69 days after transplantation in group 4 and 80 days after transplantation in group 5, whereas it is> 87 days in group 6 and group 7, which is delayed. It was.
From the above results, composition A has a growth inhibitory effect on Capan-1 tumor cells transplanted subcutaneously in nude mice in combination with Abx, and the growth inhibitory effect is higher than that in combination with Gem and Abx. Indicated.
Claims (9)
- リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物とタキサン系抗腫瘍剤とを組み合わせてなる腫瘍治療剤。 A tumor therapeutic agent comprising a combination of a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent.
- タキサン系抗腫瘍剤がパクリタキセルもしくはその塩またはナブパクリタキセルである、請求項1に記載の腫瘍治療剤。 The tumor therapeutic agent according to claim 1, wherein the taxane antitumor agent is paclitaxel or a salt thereof or nabupaclitaxel.
- タキサン系抗腫瘍剤がナブパクリタキセルである、請求項1または2に記載の腫瘍治療剤。 The tumor therapeutic agent according to claim 1 or 2, wherein the taxane antitumor agent is nabupaclitaxel.
- リポソームを構成する脂質の合計量に対するコレステロール類の含有率が10mol%~35mol%であり、リポソームの内水相の浸透圧がリポソームの外水相の浸透圧に対して2倍~8倍である、請求項1~3のいずれか一項に記載の腫瘍治療剤。 The content of cholesterol with respect to the total amount of lipids constituting the liposome is 10 to 35 mol%, and the osmotic pressure of the inner aqueous phase of the liposome is 2 to 8 times the osmotic pressure of the outer aqueous phase of the liposome. The tumor therapeutic agent according to any one of claims 1 to 3.
- リポソームがシングルラメラである請求項1~4のいずれか一項に記載の腫瘍治療剤。 The tumor therapeutic agent according to any one of claims 1 to 4, wherein the liposome is a single lamella.
- 血漿中におけるリポソーム組成物からのゲムシタビンまたはその塩の放出速度が10質量%/24hr~70質量%/24hrである、請求項1~5のいずれか一項に記載の腫瘍治療剤。 The tumor therapeutic agent according to any one of claims 1 to 5, wherein a release rate of gemcitabine or a salt thereof from the liposome composition in plasma is 10 mass% / 24 hr to 70 mass% / 24 hr.
- リポソームを構成する脂質が水素添加大豆ホスファチジルコリン、1、2-ジステアロイル-3-ホスファチジルエタノールアミン-ポリエチレングリコール、およびコレステロールを含む、請求項1~6のいずれか一項に記載の腫瘍治療剤。 The tumor therapeutic agent according to any one of claims 1 to 6, wherein the lipid constituting the liposome comprises hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol.
- リポソームの平均粒子径が2nm~200nmである、請求項1~7のいずれか一項に記載の腫瘍治療剤。 The tumor therapeutic agent according to any one of claims 1 to 7, wherein the average particle size of the liposome is 2 nm to 200 nm.
- リポソームにゲムシタビンまたはその塩を内包したリポソーム組成物およびタキサン系抗腫瘍剤を含むキット。 A kit comprising a liposome composition in which gemcitabine or a salt thereof is encapsulated in a liposome and a taxane antitumor agent.
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16862068.0A EP3372232B1 (en) | 2015-11-02 | 2016-11-01 | Tumor therapeutic agent comprising gemcitabine liposome composition and kit |
CN201680064060.7A CN108348538B (en) | 2015-11-02 | 2016-11-01 | Tumor therapeutic drug containing gemcitabine liposome composition and kit |
DK16862068.0T DK3372232T3 (en) | 2015-11-02 | 2016-11-01 | TUMOR THERAPEUTIC COMPREHENSIVE COMPOSITION GEMCITABINE LIPOSOME COMPOSITION AND KIT |
JP2017548769A JP6602886B2 (en) | 2015-11-02 | 2016-11-01 | Tumor therapeutic agent and kit comprising gemcitabine liposome composition |
KR1020187012568A KR102084340B1 (en) | 2015-11-02 | 2016-11-01 | Tumor Therapeutics and Kits Including Gemcitabine Liposomal Composition |
CN202010466892.XA CN111632030B (en) | 2015-11-02 | 2016-11-01 | Method for producing liposome composition containing gemcitabine or salt thereof |
ES16862068T ES2869283T3 (en) | 2015-11-02 | 2016-11-01 | Antitumor therapeutic agent containing gemcitabine liposome composition and kit |
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US16/808,004 US11166914B2 (en) | 2015-11-02 | 2020-03-03 | Tumor therapeutic agent and kit containing gemcitabine liposome composition |
US17/184,928 US20210275453A1 (en) | 2015-11-02 | 2021-02-25 | Tumor therapeutic agent and kit containing gemcitabine liposome composition |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019244979A1 (en) * | 2018-06-20 | 2019-12-26 | 富士フイルム株式会社 | Combination medication containing liposome composition encapsulating drug and immune checkpoint inhibitor |
WO2019244978A1 (en) * | 2018-06-20 | 2019-12-26 | 富士フイルム株式会社 | Combined medicine comprising gemcitabine-encapsulated liposome composition and immune checkpoint blockade |
WO2020071349A1 (en) * | 2018-10-01 | 2020-04-09 | 富士フイルム株式会社 | Combination medicine comprising drug-encapsulating liposome composition and platinum preparation |
WO2021201267A1 (en) * | 2020-04-03 | 2021-10-07 | 富士フイルム株式会社 | Antitumor agent |
US11413244B2 (en) | 2017-03-31 | 2022-08-16 | Fujifilm Corporation | Liposome composition and pharmaceutical composition |
US11684575B2 (en) | 2014-04-30 | 2023-06-27 | Fujifilm Corporation | Liposome composition and method for producing same |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MA43183A (en) | 2015-11-02 | 2018-09-12 | Fujifilm Corp | ANTITUMOR THERAPEUTIC AGENT CONTAINING A LIPOSOMAL COMPOSITION BASED ON GEMCITABINE AND ASSOCIATED KIT |
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CN111035616B (en) * | 2019-12-30 | 2022-03-22 | 上海景峰制药有限公司 | Gemcitabine liposome and preparation method and application thereof |
WO2023179423A1 (en) * | 2022-03-25 | 2023-09-28 | 四川科伦药物研究院有限公司 | Gemcitabine liposome pharmaceutical composition, preparation method therefor and use thereof |
WO2023186923A1 (en) | 2022-03-30 | 2023-10-05 | Meta Materials Inc. | Implanted agent delivery system |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005021012A1 (en) * | 2003-08-29 | 2005-03-10 | Terumo Kabushiki Kaisha | Drug carrier having gemcitabine enclosed therein |
US20050249795A1 (en) * | 2002-08-23 | 2005-11-10 | Neopharm, Inc. | Gemcitabine compositions for better drug delivery |
WO2014110555A1 (en) * | 2013-01-14 | 2014-07-17 | Chemo-Enchanced Llc | Compositions and methods for treating cancer |
JP2015514109A (en) * | 2012-04-04 | 2015-05-18 | ハロザイム インコーポレイテッド | Combination treatment of anti-hyaluronan and tumor-targeted taxane |
WO2015166985A1 (en) * | 2014-04-30 | 2015-11-05 | 富士フイルム株式会社 | Liposome composition and method for producing same |
WO2015166987A1 (en) * | 2014-04-30 | 2015-11-05 | 富士フイルム株式会社 | Liposome composition and production method therefor |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5049392A (en) * | 1989-01-18 | 1991-09-17 | The Liposome Company, Inc. | Osmotically dependent vesicles |
US20060165744A1 (en) * | 2003-05-22 | 2006-07-27 | Neopharm, Inc | Combination liposomal formulations |
WO2005107712A1 (en) | 2004-05-03 | 2005-11-17 | Hermes Biosciences, Inc. | Liposomes useful for drug delivery |
TW200726485A (en) * | 2005-07-01 | 2007-07-16 | Alza Corp | Liposomal delivery vehicle for hydrophobic drugs |
CA2631243A1 (en) * | 2005-12-08 | 2007-06-14 | Wyeth | Liposomal compositions |
US8119156B2 (en) * | 2006-10-24 | 2012-02-21 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
CN101209243B (en) | 2006-12-29 | 2010-12-08 | 石药集团中奇制药技术(石家庄)有限公司 | Liposome medicament and preparation thereof |
CN100496609C (en) * | 2006-12-30 | 2009-06-10 | 上海艾力斯医药科技有限公司 | Stable liposome composition |
CA2691540A1 (en) * | 2007-06-22 | 2008-12-31 | Innovative Surface Technologies, Inc. | Stimuli responsive nanofibers |
CN101878229A (en) * | 2007-09-28 | 2010-11-03 | 巴塞尔大学医院 | Immunoliposomes for treatment of cancer |
US8079820B2 (en) * | 2008-12-18 | 2011-12-20 | General Electric Company | Blade module, a modular rotor blade and a method for assembling a modular rotor blade |
EP2394640A1 (en) * | 2010-05-21 | 2011-12-14 | MediGene AG | Improved liposomal formulations of lipophilic compounds |
EP2656835B1 (en) * | 2011-03-25 | 2016-06-29 | Terumo Kabushiki Kaisha | Long-lasting controlled-release liposome composition and method for producing same |
US8987224B2 (en) * | 2011-08-05 | 2015-03-24 | Baylor College Of Medicine | MicroRNA-198 as a tumor suppressor in pancreatic cancer |
CA2852564A1 (en) * | 2011-10-31 | 2013-05-10 | Mallinckrodt Llc | Combinational liposome compositions for cancer therapy |
EP2604253A1 (en) * | 2011-12-13 | 2013-06-19 | Otto Glatter | Water-in-oil emulsions and methods for their preparation |
CN102784107B (en) * | 2012-05-17 | 2015-04-22 | 江苏豪森药业股份有限公司 | Gemcitabine or salt liposome thereof, and preparation method and application thereof |
CA2894846A1 (en) * | 2012-12-12 | 2014-06-19 | Temple University - Of The Commonwealth System Of Higher Education | Compositions and methods for treatment of cancer |
EP2964201B1 (en) | 2013-03-05 | 2024-02-14 | The Regents of the University of California | Lipid bilayer coated mesoporous silica nanoparticles with a high loading capacity for one or more anticancer agents |
MA43183A (en) | 2015-11-02 | 2018-09-12 | Fujifilm Corp | ANTITUMOR THERAPEUTIC AGENT CONTAINING A LIPOSOMAL COMPOSITION BASED ON GEMCITABINE AND ASSOCIATED KIT |
US10940112B2 (en) * | 2016-05-04 | 2021-03-09 | L.E.A.F. Holdings Group Llc | Targeted liposomal gemcitabine compositions and methods thereof |
-
2016
- 2016-11-01 MA MA043183A patent/MA43183A/en unknown
- 2016-11-01 WO PCT/JP2016/082415 patent/WO2017078008A1/en active Application Filing
- 2016-11-01 CN CN202010466486.3A patent/CN111437259A/en active Pending
- 2016-11-01 KR KR1020187012568A patent/KR102084340B1/en active IP Right Grant
- 2016-11-01 EP EP16862068.0A patent/EP3372232B1/en active Active
- 2016-11-01 RU RU2020137385A patent/RU2768178C2/en active
- 2016-11-01 PL PL16862068T patent/PL3372232T3/en unknown
- 2016-11-01 ES ES16862068T patent/ES2869283T3/en active Active
- 2016-11-01 CN CN201680064060.7A patent/CN108348538B/en active Active
- 2016-11-01 JP JP2017548769A patent/JP6602886B2/en active Active
- 2016-11-01 RU RU2018119680A patent/RU2738365C2/en active
- 2016-11-01 CN CN202010466892.XA patent/CN111632030B/en active Active
- 2016-11-01 RU RU2020137384A patent/RU2761620C2/en active
- 2016-11-01 DK DK16862068.0T patent/DK3372232T3/en active
-
2018
- 2018-05-01 US US15/967,970 patent/US11166913B2/en active Active
-
2020
- 2020-03-03 US US16/808,004 patent/US11166914B2/en active Active
-
2021
- 2021-02-25 US US17/184,928 patent/US20210275453A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050249795A1 (en) * | 2002-08-23 | 2005-11-10 | Neopharm, Inc. | Gemcitabine compositions for better drug delivery |
WO2005021012A1 (en) * | 2003-08-29 | 2005-03-10 | Terumo Kabushiki Kaisha | Drug carrier having gemcitabine enclosed therein |
JP2015514109A (en) * | 2012-04-04 | 2015-05-18 | ハロザイム インコーポレイテッド | Combination treatment of anti-hyaluronan and tumor-targeted taxane |
WO2014110555A1 (en) * | 2013-01-14 | 2014-07-17 | Chemo-Enchanced Llc | Compositions and methods for treating cancer |
WO2015166985A1 (en) * | 2014-04-30 | 2015-11-05 | 富士フイルム株式会社 | Liposome composition and method for producing same |
WO2015166987A1 (en) * | 2014-04-30 | 2015-11-05 | 富士フイルム株式会社 | Liposome composition and production method therefor |
Non-Patent Citations (6)
Title |
---|
COSCO DONATO ET AL.: "In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer", CANCER CHEMOTHER PHARMACOL, vol. 64, no. 5, 2009, pages 1009 - 1020, XP019738527 * |
COSCO DONATO ET AL.: "Liposomes as multicompartmental carriers for multidrug delivery in anticancer chemotherapy", DRUG DELIVERY AND TRANSLATIONAL RESEARCH, vol. 1, no. 1, 2011, pages 66 - 75, XP055384113 * |
HIDEKI UENO ET AL.: "Systemic chemotherapy for advanced pancreatic cancer", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 252, no. 8, 21 February 2015 (2015-02-21), pages 887 - 892, XP009506356 * |
LIBOIRON D. BARRY ET AL.: "Nanoscale delivery systems for combination chemotherapy", DRUG DELIVERY IN ONCOLOGY, vol. 2, 2012, pages 1013 - 1050, XP055384114 * |
See also references of EP3372232A4 * |
VON HOFF D. DANIEL ET AL.: "Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine", N ENGL J MED., vol. 369, no. 18, 2013, pages 1691 - 1703, XP055250743 * |
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ES2869283T3 (en) | 2021-10-25 |
DK3372232T3 (en) | 2021-06-07 |
KR102084340B1 (en) | 2020-03-03 |
US20180243214A1 (en) | 2018-08-30 |
CN108348538A (en) | 2018-07-31 |
RU2020137385A (en) | 2020-12-03 |
RU2018119680A (en) | 2019-12-05 |
JP6602886B2 (en) | 2019-11-06 |
RU2761620C2 (en) | 2021-12-13 |
EP3372232A1 (en) | 2018-09-12 |
RU2020137384A (en) | 2020-12-03 |
EP3372232A4 (en) | 2018-11-14 |
CN108348538B (en) | 2021-06-22 |
US11166914B2 (en) | 2021-11-09 |
RU2738365C2 (en) | 2020-12-11 |
US11166913B2 (en) | 2021-11-09 |
RU2768178C2 (en) | 2022-03-23 |
RU2018119680A3 (en) | 2019-12-05 |
CN111437259A (en) | 2020-07-24 |
RU2020137384A3 (en) | 2021-03-31 |
CN111632030A (en) | 2020-09-08 |
KR20180054873A (en) | 2018-05-24 |
US20210275453A1 (en) | 2021-09-09 |
US20200197305A1 (en) | 2020-06-25 |
CN111632030B (en) | 2023-01-17 |
EP3372232B1 (en) | 2021-04-14 |
RU2020137385A3 (en) | 2021-03-31 |
JPWO2017078008A1 (en) | 2018-08-09 |
PL3372232T3 (en) | 2021-09-27 |
MA43183A (en) | 2018-09-12 |
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